Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:19]([NH:21][NH:22][C:23]2[C:28]([F:29])=[C:27]([N:30]3[CH2:33][C:32]([CH3:39])([N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)[CH2:31]3)[N:26]=[C:25]([CH3:40])[N:24]=2)=[O:20])[CH2:8][N:9]([O:12]C2CCCCO2)[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(O)=O>O>[CH:1]1([CH2:6][C@@H:7]([C:19]([NH:21][NH:22][C:23]2[C:28]([F:29])=[C:27]([N:30]3[CH2:31][C:32]([CH3:39])([N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)[CH2:33]3)[N:26]=[C:25]([CH3:40])[N:24]=2)=[O:20])[CH2:8][N:9]([OH:12])[CH:10]=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)c(F)c(N2CC(C)(N3CCCC3)C2)n1
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)c(F)c(N2CC(C)(N3CCCC3)C2)n1
Yield: 64.8 %

Procedure:
A solution of [(2R)-2-(cyclopentylmethyl)-3-(2-{5-fluoro-2-methyl-6-[3-methyl-3-(1-pyrrolidinyl)-1-azetidinyl]-4-pyrimidinyl}hydrazino)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (118 mg) in 4:1 AcOH:water (20 mL) was stirred at room temperature for 3 days. The solvents were removed in vacuo, and the resulting crude product was purified by RP-HPLC to provide [(2R)-2-(cyclopentylmethyl)-3-(2-{5-fluoro-2-methyl-6-[3-methyl-3-(1-pyrrolidinyl)-1-azetidinyl]-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide (65 mg, 64%). LCMS: (M+H)+: 478.1.
Reaction SMILES: CNC.C([Li])CCC.CCCCCC.CN(C)P(=O)(N(C)C)N(C)C.[Br:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[C:29]([CH3:35])[CH:28]=1.[C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1)#[N:37].[ClH:44]>O1CCCC1>[ClH:44].[NH2:32][C:31]1[C:30]2[C:29](=[CH:28][C:27]([Br:26])=[CH:34][CH:33]=2)[CH:35]=[C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)[N:37]=1
Reactant: Cc1cc(Br)ccc1C#N
Reactant: N#Cc1ccccn1
Agent: CNC
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Nc1nc(-c2ccccn2)cc2cc(Br)ccc12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 10.5 g (0.23 mol) of dimethylamine in 80 ml of tetrahydrofuran, 100 ml of 15% (w/v) n-butyl lithium in hexane (0.23 mol) were added under a nitrogen atmosphere. After 30 minutes, 18 g (0.1 mol) of hexamethylphosphoric triamide (HMPTA) were added, after which the mixture was cooled to -78° C. To the light-yellow solution obtained, 19.6 g (0.1 mol) of 4-bromo-2-methylbenzonitrile in 60 ml of anhydrous tetrahydrofuran were added in the course of 10 minutes, after which the deep red solution was stirred for another 15 minutes. Subsequently 15.7 g (0.15 mol) of 2-cyanopyridine in 60 ml of anhydrous tetrahydrofuran was added dropwise in the course of 10 minutes. The reaction mixture was heated to 60° C. for one hour and it was then hydrolysed with 400 ml of 10% (w/v) hydrochloric acid. The yellow precipitate obtained was filtered off, the filtrate was washed with diethyl ether, neutralised with sodium hydroxide and extracted with chloroform. The solvent was distilled off from the extract and the residue was sublimed. The product obtained was converted into the hydrochloride, as described in Example VII, and the hydrochloride was combined with the yellow precipitate and crystallised from ethanol. 1-Amino-6-bromo-3-(2-pyridyl)isoquinoline hydrochloride was obtained, melting point 257.5° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([N+:24]([O-])=O)[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>N1C=CC=CC=1.O>[NH2:24][C:16]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:9]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13]
Reactant: O=C(O)c1cc(NCc2ccccc2)c(-c2ccccc2)c([N+](=O)[O-])c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: Nc1cc(C(=O)O)cc(NCc2ccccc2)c1-c1ccccc1

Procedure:
To a stirred solution of 3-benzylamino-5-nitro-4-phenylbenzoic acid (3.0 g) in a mixture of pyridine (15 ml) and water (15 ml), sodium dithionite (6.0 g) is added in portions during about 15 minutes. The mixture is heated on a steam bath for about 30 minutes, and is then evaporated in vacuo. The residue is treated with cold 1 N acetic acid (about 50 ml) and after cooling, the resulting precipitate is collected by filtration, washed with water and dried. After recrystallization twice from aqueous ethanol, 5-amino-3-benzylamino-4-phenylbenzoic acid is obtained with a melting point of 179°-181° C.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[CH:14][C:13]([N:16]([CH3:36])[C:17](=[O:35])[C:18]([C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=3)([CH3:20])[CH3:19])=[C:12]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=3[CH3:44])[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2].[CH3:45][Si]([N-][Si](C)(C)C)(C)C.[K+].IC.C(OCC)(=O)C>O1CCCC1>[C:1]([N:4]([CH3:45])[C@@H:5]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[CH:14][C:13]([N:16]([CH3:36])[C:17](=[O:35])[C:18]([C:21]3[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[C:23]([C:31]([F:32])([F:33])[F:34])[CH:22]=3)([CH3:20])[CH3:19])=[C:12]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=3[CH3:44])[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(=O)N[C@@H]1CCN(c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)C1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CI
Product: CC(=O)N(C)[C@@H]1CCN(c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To a solution of 146 mg (0.234 mmol) (R)—N-[6-(3-acetylamino-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide in 5 ml tetrahydrofuran were added dropwise at room temperature 0.31 ml (0.28 mmol) of a 0.91 N potassium bis(trimethylsilyl)amide solution in tetrahydrofuran. After stirring at room temperature for 30 min. 43 mg (30 mmol) iodomethane were added. The reaction mixture was stirred at room temperature for 18 h, followed by dilution with 10 ml ethyl acetate and washing with 10 ml saturated sodium carbonate solution. The combined organic layers were dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography to give 130 mg (87%) of the title compound as a white foam.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)=O)=[C:4]([CH3:14])[CH:3]=1.S(C)C.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:8][CH:9]2[CH2:10][CH2:11]2)=[C:4]([CH3:14])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)NC1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CSC
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1CNC1CC1
Temperature: 60 °C
Reaction time: 17 h

Procedure:
To a solution of 4-bromo-N-cyclopropyl-2-methyl-benzamide (Intermediate 157, 1.81 g, 7.12 mmols) in THF (12 mL) was added BH3.SMe2(1.08 g, 14.24 mmols). The solution was heated to 60° C. for 6 hours, cooled to room temperature and carefully treated with saturated aqueous Na2CO3(30 mL) and stirred for 17 hours. This mixture was extracted with EtOAc and the combined organic layers were washed with H2O, saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The title compound was isolated by column chromatography (10-15% EtOAc-hexanes).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[CH:12]=[C:11]([CH:13]=O)[N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.C(OP([CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])(OCC)=O)C.CN(C)C=O.[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[O:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[CH:12]=[C:11](/[CH:13]=[CH:46]/[C:47]([O:49][CH2:50][CH3:51])=[O:48])[N:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1cc(COc2cc(C=O)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)c(OC)c2)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
To a mixture of 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazole-5-carbaldehyde (600 mg), ethyl diethylphosphonoacetate (300 mg) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 52.0 mg) at 0° C., and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl (E)-3-(3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazol5-yl)-2-propenoate (590 mg, yield 86%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:4, v/v). The crystals were recrystallized from ethyl acetate-hexane. melting point: 121-122° C.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[N:17][C:5]2[NH:6][C@@H:7]([CH3:16])[CH2:8][N:9]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[C:4]=2[CH:3]=1.ClCCCl.C(N(CC)C(C)C)(C)C.[CH3:32][NH:33][C:34](Cl)=[O:35]>C(OCC)(=O)C>[Br:1][C:2]1[CH:18]=[N:17][C:5]2[N:6]([C:34](=[O:35])[NH:33][CH3:32])[C@@H:7]([CH3:16])[CH2:8][N:9]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[C:4]=2[CH:3]=1
Reactant: CC(C)OC(=O)N1C[C@H](C)Nc2ncc(Br)cc21
Reactant: CNC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CNC(=O)N1c2ncc(Br)cc2N(C(=O)OC(C)C)C[C@@H]1C
Temperature: 50 °C

Procedure:
A reaction vial was charged with (S)-isopropyl 7-bromo-3-methyl-3,4-dihydropyrido[2,3-b]pyrazine-1(2H)-carboxylate (0.02 mmol), 1,2-dichloroethane (0.10 mL), and N,N-diisopropylethylamine (0.25 mL, 0.14 mmol). Methylcarbamic chloride (1.0 M solution in 1,2-dichloroethane, 0.120 mL, 0.120 mmol) was added, and the reaction was heated at 50° C. overnight. N,N-Diisopropylethylamine (0.25 mL, 0.14 mmol) and methylcarbamic chloride (1.0 M solution in 1,2-dichloroethane, 0.120 mL, 0.120 mmol) were added, and the reaction was heated at 80° C. overnight. The reaction was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The aqueous layer was separated and extracted with ethyl acetate and the combined organic layers were concentrated under a stream of nitrogen to afford (S)-isopropyl 7-bromo-3-methyl-4-(methylcarbamoyl)-3,4-dihydropyrido[2,3-b]pyrazine-1(2H)-carboxylate which was used in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.C[N+]1([O-])CC[O:16]CC1>ClCCl>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([OH:16])=[CH:5][CH:4]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: COc1ccc(B(O)O)cn1
Solvent: ClCCl
Product: COc1ccc(O)cn1
Temperature: 50 °C
Reaction time: 14 h

Procedure:
At RT, 50 g (327 mmol) of 6-methoxypyridin-3-ylboronic acid were added to a solution of 46.0 g (392 mmol) of N-methylmorpholine N-oxide in 500 ml of dichloromethane, and the mixture was stirred at 50° C. for 14 h. Additional N-methylmorpholine N-oxide was added until the reaction had gone to completion. The reaction mixture was concentrated under reduced pressure and the crude product was purified by flash chromatography (silica gel 60, cyclohexane/ethyl acetate mixtures). Yield: 32.9 g (80% of theory)
Reaction SMILES: [OH-].[Na+].[OH:3][CH:4]([C:6]1[CH:7]=[C:8]([C:24]([O:26]C)=[O:25])[CH:9]=[C:10]2[C:15]=1[O:14][C:13]([N:16]1[CH2:21][CH2:20][O:19][C@H:18]([CH3:22])[CH2:17]1)=[CH:12][C:11]2=[O:23])[CH3:5].O.Cl>CO>[OH:3][CH:4]([C:6]1[CH:7]=[C:8]([C:24]([OH:26])=[O:25])[CH:9]=[C:10]2[C:15]=1[O:14][C:13]([N:16]1[CH2:21][CH2:20][O:19][C@H:18]([CH3:22])[CH2:17]1)=[CH:12][C:11]2=[O:23])[CH3:5]
Reactant: COC(=O)c1cc(C(C)O)c2oc(N3CCO[C@H](C)C3)cc(=O)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(O)c1cc(C(=O)O)cc2c(=O)cc(N3CCO[C@H](C)C3)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
NaOH (3.56 mL, 7.11 mmol) was added to a stirred suspension of methyl 8-(1-hydroxyethyl)-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylate (988 mg, 2.84 mmol) in MeOH (10 mL)/water (10 mL). The resulting mixture was stirred at RT for 1 hour then acidified to pH 2-3 with a 2N aq. HCl (7.68 mL, 7.68 mmol). The resulting precipitate was collected by filtration, washed with diethyl ether and dried to afford 8-(1-hydroxyethyl)-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylic acid (900 mg, 95%) as a grey solid, which was used without further purification. Mass Spectrum: M+H+ 334.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:4]2([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:3]1[C:12]([OH:14])=[O:13].C([O-])([O-])=O.[K+].[K+].[CH2:21](I)[CH3:22].Cl>CN(C=O)C>[CH2:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:4]2([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:3]1[C:12]([O:14][CH2:21][CH3:22])=[O:13]
Reactant: C=C1CCCC2(CCCC2)C1C(=O)O
Reactant: CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C1CCCC2(CCCC2)C1C(=O)OCC
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
At 5° C., a solution of the previously obtained 7-methylenespiro[4.5]decane-6-carboxylic acid (1.2 g, 6.2 mmol) in DMF (30 ml) was treated with K2CO3 (0.94 g, 6.8 mmol). The resulting mixture was stirred for 30 min., treated with ethyl iodide (0.75 ml, 9.3 mmol), stirred at 20° C. for 2 h, poured into cold 2N aqueous HCl (20 ml), and extracted twice with hexane (50 ml). The combined organic phases were washed with water (50 ml), with a saturated aqueous solution of NaCl (50 ml), dried (MgSO4), and concentrated. FC (90 g SiO2, hexane/MTBE 98:2) of the crude product (1.23 g) gave ethyl 7-methylenespiro[4.5]decane-6-carboxylate (0.69 g, 50%). Boiling point: 90° C. (0.08 mbar).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:18]3=[N:19][C:20]4[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([CH:27]([O:32][CH:33]([F:35])[F:34])[C:28]([F:31])([F:30])[F:29])[C:21]=4[N:17]3[CH2:16][CH2:15][CH2:14]2)=[C:9]([CH3:36])[N:8]=1)(=O)=O.[CH3:39][N:40]1[CH2:45][CH2:44]C[CH2:42][CH2:41]1.C[N:47](C)C=O>O>[Cl:26][C:25]1[C:20]2[N:19]=[C:18]3[N:13]([C:10]4[C:9]([CH3:36])=[N:8][C:7]([N:47]5[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]5)=[CH:12][CH:11]=4)[CH2:14][CH2:15][CH2:16][N:17]3[C:21]=2[C:22]([CH:27]([O:32][CH:33]([F:34])[F:35])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:24]=1
Reactant: CN(C)C=O
Reactant: CN1CCCCC1
Reactant: Cc1nc(OS(=O)(=O)C(F)(F)F)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Solvent: O
Product: Cc1nc(N2CCN(C)CC2)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Temperature: 80 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
To a solution of 5-{9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-3,4-dihydropyrimido[1,2-a]benzimidazol-1(2H)-yl}-6-methylpyridin-2-yl trifluoromethanesulfonate (113.7 mg, 0.191 mmol) in N,N-dimethylformamide (1.5 mL) was added 1-methylpiperadine (106.0 μL, 0.956 mmol). The reaction mixture was stirred at 80° C. for 18 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic layer was washed with water (×2) and brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by basic silica gel column chromatography eluting with a 20-60% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from ethyl acetate/n-hexane to give a title compound as a colorless powder (76.8 mg, 0.141 mmol, 74%).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:4]=1[C:19]([OH:21])=O)#[N:2].F[P-](F)(F)(F)(F)F.[N:29]1([O:38][C:39](N(C)C)=[N+](C)C)[C:33]2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CNOC>CN(C)C=O>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:4]=1[C:19]([N:29]([O:38][CH3:39])[CH3:33])=[O:21])#[N:2]
Reactant: N#Cc1c(C(=O)O)n(-c2cccc(F)c2)c2ccccc12
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1c(C#N)c2ccccc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.7 %

Procedure:
A mixture of 3-cyano-1-(3-fluorophenyl)-1H-indole-2-carboxylic acid (0.12 g, 0.43 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.32 g, 0.86 mmol) and N,N-diisopropylethylamine (0.37 mL, 2.1 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 10 minutes. N,O-Dimethylhydroxylamine hydrochloride (63 mg, 0.64 mmol) was added and the resulting suspension was stirred at room temperature overnight. The mixture was quenched with water and extracted with EtOAc. The extracts were combined, dried over MgSO4, concentrated, and purified on silica gel (eluting with 0-25% EtOAc/hexane) to give the desired product (90 mg, 65%). LCMS calculated for C18H15FN3O2(M+H)+: m/z=324.1. Found: 324.0.
Reaction SMILES: [CH:1]1([Si:6](OCC)([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:16]([OH:20])([CH3:19])([CH3:18])[CH3:17].[O-]CC.[Na+].C[Si](C)(C)Cl>>[C:16]([O:20][Si:6]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)O
Reactant: CCO[Si](OCC)(OCC)C1CCCC1
Agent: CC[O-]
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Product: CCO[Si](OCC)(OC(C)(C)C)C1CCCC1
Yield: 64.2 %

Procedure:
In a 500 ml three-neck flask provided with a magnetic stirrer and a reflux condenser were charged 29.3 g (0.129 mole) of cyclopentyl triethoxysilane, 165.9 g (2.24 mole) of tert-butyl alcohol and 2.06 g (30.3 m mole) of sodium ethoxide, which were then reacted with each other in an oil bath of 85° C. for 24 hours under stirring. Then, trimethylchlorosilane was added to neutralize the alkali. Then, 21.6 g (0.0828 mole) of tert-butoxy cyclopentyl diethoxysilane were obtained by vacuum distillation. Its structure was confirmed as in Example 1. The yield was 64%.
Reaction SMILES: C[Mg]Cl.[CH3:4][Zn]C.[CH2:7]([C@@H:10]1[CH2:14][C:13](=[O:15])[CH:12]=[CH:11]1)[CH2:8][CH3:9]>CCOCC.C1(C)C=CC=CC=1.C1COCC1>[CH3:4][C@H:11]1[C@H:10]([CH2:7][CH2:8][CH3:9])[CH2:14][C:13](=[O:15])[CH2:12]1
Reactant: CCC[C@H]1C=CC(=O)C1
Reactant: C[Zn]C
Agent: C[Mg]Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCC[C@@H]1CC(=O)C[C@H]1C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 63 %

Procedure:
Methylmagnesium chloride (7.1 ml of a 3M solution in ether, 21.3 mmol) was added slowly to a stirred solution of dimethylzinc (5.3 ml of a 2M solution in toluene, 10.6 mmol) in THF (80ml) under argon at 0° C. After 30 minutes the mixture was cooled to −78° C. and 2 (1.2 g, 9.7 mmol) in THF (45 ml) was added dropwise over 1 hour. The reaction mixture was stirred for 20 minutes and then quenched by the addition of saturated ammonium chloride solution (20 ml). The reaction mixture was allowed to warm to room temperature, diluted with 1N hydrochloric acid (100 ml) and extracted with ether (3×200 ml). The organic layer was washed with brine (200 ml), dried (MgSO4) and the solvent was removed under reduced pressure to yield 4 as a solution in toluene which was purified by column chromatography (SiO2, pentane-ether, 1:0 to 9:1 to give the cyclopentanone 4 (0.86 g, 63%). νmax(CDCl3)/cm−1 1733 (C═O).
Reaction SMILES: CO[C:3](=[O:17])[C:4]([C:6]1[CH:7]=[C:8]([CH3:16])[CH:9]=[C:10]2[C:14]=1[N:13]([CH3:15])[CH:12]=[CH:11]2)=[O:5].[F:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23]([CH2:28][C:29]([NH2:31])=[O:30])=[CH:24][NH:25]2)=[CH:21][CH:20]=1.CC(C)([O-])C.[K+].C1COCC1.Cl>CN(C=O)C>[CH3:15][N:13]1[C:14]2[C:10](=[CH:9][C:8]([CH3:16])=[CH:7][C:6]=2[C:4](=[O:5])[C:3]([NH:31][C:29](=[O:30])[CH2:28][C:23]2[C:22]3[C:26](=[CH:27][C:19]([F:18])=[CH:20][CH:21]=3)[NH:25][CH:24]=2)=[O:17])[CH:11]=[CH:12]1
Reactant: NC(=O)Cc1c[nH]c2cc(F)ccc12
Reactant: COC(=O)C(=O)c1cc(C)cc2ccn(C)c12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)C(=O)NC(=O)Cc2c[nH]c3cc(F)ccc23)c2c(ccn2C)c1
Temperature: 25 °C
Reaction time: 11 h
Yield: 21.7 %

Procedure:
To a mixture of (1,5-dimethyl-1H-indol-7-yl)-oxo-acetic acid methyl ester (0.51 g, 2.21 mmol) and 2-(6-fluoro-1H-indol-3-yl)-acetamide (0.38 g, 2 mmol) in DMF (20 mL) was added a solution of potassium tert-butoxide in THF (1.0 M, 8.0 mL, 8.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 11 h, treated with concentrated hydrochloric acid (2 mL) and then heated at 50° C. for 2 h. The mixture was cooled to room temperature, extracted with ethyl acetate and the extract was washed with water, saturated aqueous sodium bicarbonate and brine dried (sodium sulfate), filtered and evaporated. Flash column chromatography on silica gel eluting with chloroform and acetone gave 2-(1,5-dimethyl-1H-indol-7-yl)-N-[2-(6-fluoro-1H-indol-3-yl)-acetyl]-2-oxo-acetamide (170 mg, 23%) and 3-(1,5-dimethyl-1H-indol-7-yl)-4-(6-fluoro-1H-indol-3-yl)-pyyrole-2,5-dione (340 mg, 45.5%). 1H NMR (d6-DMSO, 400 MHz) δ 2.26 (s, 3H), 3.58 (s, 3H), 6.36 (d, J=3.13 Hz, 1H), 6.40˜6.45 (m, 2H), 6.73 (s, 1H), 7.11 (dd, J1=2.34 Hz, J2=9.38 Hz, 1H), 7.16 (d, J=3.13 Hz, 1H), 7.7.39 (s, 1H), 7.80 (d, J=3.13 Hz, 1H), 11.14 (s, 1H), 11.82 (s, 1H); MS (ES, m/z): C22H16FN3O2: 374.2 (M++1); 372.2 (M+−1).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH:4]=[CH:3][C:2]1=[O:7].FC(F)(F)C(O)=O.[CH2:15]([N:22]([CH2:28]OC)[CH2:23][Si](C)(C)C)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl>[CH2:15]([N:22]1[CH2:28][C@@H:3]2[C:2](=[O:7])[NH:1][C:5](=[O:6])[C@@H:4]2[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=C1C=CC(=O)N1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC(=O)[C@@H]2CN(Cc3ccccc3)C[C@H]12
Temperature: 25 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
1H-Pyrrole-2,5-dione (8.0 g, 82 mmol) in dichloromethane (220 mL) at 0° C. was treated with trifluoroacetic acid (0.93 g, 8.2 mmol) and then treated with N-benzyl-N-(methoxymethyl)-N-[(trimethylsilyl)methyl]amine (26 g, 110 mmol) prepared according to (Organic Synthesis (1988), 67, 133-135) in dichloromethane (15 mL) dropwise over 30 minutes. The mixture was allowed to stir at ambient temperature overnight and then concentrated under reduced pressure. The residue was triturated with ethyl acetate:hexane (3:7, 50 mL), cooled to 0° C. and filtered to provide the title compound as a white solid (5.86 g, 31% yield). MS (DCI/NH3) m/z 231 (M+H)+.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[O:11][CH:10]=[C:9]([C:19](O)=[O:20])[C:8]2=[O:22])(=[O:3])[CH3:2].C1C=CC=CC=1.S(Cl)([Cl:31])=O.CN(C)C=O>CCCCCC>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[O:11][CH:10]=[C:9]([C:19]([Cl:31])=[O:20])[C:8]2=[O:22])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1cc2occ(C(=O)O)c(=O)c2cc1OC(C)=O
Solvent: CCCCCC
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc2occ(C(=O)Cl)c(=O)c2cc1OC(C)=O
Temperature: 25 °C
Yield: 90.2 %

Procedure:
A mixture of 6,7-diacetoxychromone-3-carboxylic acid (18.4 g), benzene (450 ml), 8.6 g of thionyl chloride (8.6 g) and dimethylformamide (3 ml) was refluxed for one hour and then cooled to room temperature. To the reaction mixture was added hexane (300 ml) and the precipitate separated out was recovered by filtration. There was thus obtained the desired product (17.6 g).